The highly polymorphic genes in the major histocompatibility complex (MHC) encode products which regulate the immune response. Studies were undertaken to identify position and extent of polymorphisms in newly described MHC genes, to determine if individual alleles or combinations of alleles of MHC genes were associated with diseases with known autoimmune pathogenesis or with the progression to disease in HIV- infected individuals. Polymorphisms in the recently described DMbeta genes were found in the first exon in contrast to the genes encoding HLA class I and II where the polymorphism is located in the second and third exons. Other genes under study are TAP1 and TAP2, whose products transport peptides across the endoplasmic reticulum where the peptides are assembled with HLA class I molecules and are presented at the cell surface to be recognized by cytotoxic T-cells. TAP allele frequencies were determined in individuals with Reiter's syndrome (RS) where the presence of another MHC allele, HLA-B27, is diagnostic. Specific TAP1 and TAP2 alleles were significantly higher in RS compared to the frequency of these alleles in HLA-27+ disease-free controls, indicating that combinations of alleles with interdependent function contribute to disease outcome. HLA haplotype sharing was found to be significantly correlated with concordance or discordance in disease progression in 94 human immunodeficiency virus-1 (HIV-1)-infected sibling pairs, indicating that the MHC plays an important role in HIV-1 disease progression. Specific alleles and allele combinations of the HLA class I, II and TAP genes were found to be highly associated with the duration of the disease-free interval in 122 HIV-1-infected homosexual males that have been followed since 1982. These results were replicated in another cohort of HIV-1-infected men that became infected and have developed AIDS since 1985. The results demonstrate that specific HLA alleles contribute to/or regulate the rate of disease progression after HIV-1 infection.